RESUMEN
A chromatography-free asymmetric synthesis of GDC-6036 (1) was achieved via a highly atroposelective Negishi coupling of aminopyridine 5 and quinazoline 6b catalyzed by 0.5 mol % [Pd(cin)Cl]2 and 1 mol % (R,R)-Chiraphite to afford the key intermediate (Ra)-3. An alkoxylation of (Ra)-3 with (S)-N-methylprolinol (4) and a global deprotection generates the penultimate heterobiaryl intermediate 2. A controlled acrylamide installation by stepwise acylation/sulfone elimination and final adipate salt formation and crystallization delivered high-purity GDC-6036 (1).
RESUMEN
Recently we have documented research efforts aimed at new classes of oxetanes as well as spiroheteroalicyclic ring systems (which we have termed 'Compact Modules') designed to expand the palette of tailored module scaffolds available to medicinal chemists, which constitute an important role for synthetic chemistry in the drug discovery process. An essential component for this process is to provide access to specific molecular topologies with functional group diversity, essential for generating leads that discriminate among biological targets, therefore promoting selectivity and enhancing the safety profile of the final clinical candidates.
Asunto(s)
Azetidinas/química , Éteres Cíclicos/química , Compuestos de Espiro/química , Azetidinas/síntesis química , Descubrimiento de Drogas , Éteres Cíclicos/síntesis química , Estructura Molecular , Compuestos de Espiro/síntesis químicaRESUMEN
Oxetanes are used in drug discovery to enable physicochemical and metabolic property enhancement for the structures to which they are grafted. An imide CâO to oxetane swap on thalidomide and lenalidomide templates provides analogs with similar physicochemical and in vitro properties of the parent drugs, with an important exception: oxetane analog 2 displays a clear differentiation with respect to human plasma stability. The prospect of limiting in vivo stability/metabolism, blocking in vivo racemization, and potentially altering teratogenicity is appealing.
Asunto(s)
Éteres Cíclicos/síntesis química , Talidomida/análogos & derivados , Talidomida/síntesis química , Animales , Descubrimiento de Drogas , Éteres Cíclicos/sangre , Éteres Cíclicos/química , Hepatocitos/metabolismo , Humanos , Lenalidomida , Ratones , Microsomas Hepáticos/metabolismo , Estructura Molecular , Ratas , Talidomida/sangre , Talidomida/químicaRESUMEN
The preparation of versatile azaspiro[3.3]heptanes carrying multiple exit vectors is disclosed. Expedient synthetic routes enable the straightforward access to these novel modules that are expected to have significance in drug discovery and design.
Asunto(s)
Compuestos Aza/síntesis química , Heptanos/síntesis química , Compuestos de Espiro/síntesis química , Éteres Cíclicos/química , Modelos Moleculares , Estructura MolecularRESUMEN
Sizable resources, both financial and human, are invested each year in the development of new pharmaceutical agents. However, despite improved techniques, the new compounds often encounter difficulties in satisfying and overcoming the numerous physicochemical and many pharmacological constraints and hurdles. Oxetanes have been shown to improve key properties when grafted onto molecular scaffolds. Of particular interest are oxetanes that are substituted only in the 3-position, since such units remain achiral and their introduction into a molecular scaffold does not create a new stereocenter. This Minireview gives an overview of the recent advances made in the preparation and use of 3-substituted oxetanes. It also includes a discussion of the site-dependent modifications of various physicochemical and biochemical properties that result from the incorporation of the oxetane unit in molecular architectures.
Asunto(s)
Diseño de Fármacos , Descubrimiento de Drogas , Éteres Cíclicos/química , Preparaciones Farmacéuticas , HumanosAsunto(s)
Compuestos Aza/síntesis química , Compuestos de Espiro/síntesis química , Antiinfecciosos/síntesis química , Antiinfecciosos/farmacología , Compuestos Aza/metabolismo , Compuestos Aza/farmacología , Descubrimiento de Drogas , Hepatocitos/metabolismo , Humanos , Estructura Molecular , Compuestos de Espiro/metabolismo , Compuestos de Espiro/farmacología , Staphylococcus aureus/efectos de los fármacosRESUMEN
Straightforward access toward previously unreported substituted, heterocyclic spiro[3.3]heptanes is disclosed. These spirocyclic systems may be considered as alternatives to 1,3-heteroatom-substituted cyclohexanes, which are otherwise insufficiently stable to allow their use in drug discovery. Conformational details are discussed on the basis of X-ray crystallographic structures.
Asunto(s)
Heptanos/síntesis química , Cristalografía por Rayos X , Heptanos/química , Modelos Moleculares , Estructura MolecularRESUMEN
Trypanothione reductase (TR) is a flavoenzyme unique to trypanosomatid parasites and a target for lead discovery programs. Various inhibitor scaffolds have emerged in the past, exhibiting moderate affinity for the parasite enzyme. Herein we show that the combination of two structural motifs of known TR inhibitors - diaryl sulfides and mepacrine - enables the simultaneous addressing of two hydrophobic patches in the active site. The binding efficacy of these conjugates is enhanced over that of the respective parent inhibitors. They show K(ic) values for the parasite enzyme down to 0.9+/-0.1 microm and exhibit high selectivity for TR over human glutathione reductase (GR). Despite their considerable molecular mass and in some cases permanent positive charges, in vitro studies revealed IC(50) values in the low micromolar to sub-micromolar range against Trypanosoma brucei rhodesiense and Trypanosoma cruzi, as well as the malaria parasite Plasmodium falciparum, which lack trypanothione metabolism. The inhibitors exhibit strong fluorescence due to their aminoacridine moiety. This feature allows visualization of the drugs in the parasite where high accumulation was observed by fluorescence microscopy even after short exposure times.
Asunto(s)
Antiprotozoarios/farmacología , Colorantes Fluorescentes/farmacología , NADH NADPH Oxidorreductasas/antagonistas & inhibidores , NADH NADPH Oxidorreductasas/metabolismo , Plasmodium falciparum/enzimología , Quinacrina/farmacología , Trypanosoma/enzimología , Aminacrina/síntesis química , Aminacrina/química , Aminacrina/farmacología , Antiprotozoarios/síntesis química , Antiprotozoarios/química , Colorantes Fluorescentes/síntesis química , Colorantes Fluorescentes/química , Glutatión Reductasa/metabolismo , Humanos , Estructura Molecular , Plasmodium falciparum/efectos de los fármacos , Unión Proteica , Quinacrina/síntesis química , Quinacrina/química , Sulfuros/síntesis química , Sulfuros/química , Sulfuros/farmacología , Tripanocidas/síntesis química , Tripanocidas/química , Tripanocidas/farmacología , Trypanosoma/efectos de los fármacosRESUMEN
A concise and scalable synthesis of a 2,6-diazaspiro[3.3]heptane building block is reported. The usefulness of this structural surrogate of piperazine is shown in arene amination reactions yielding a variety of N-Boc- N'-aryl-2,6-diazaspiro[3.3]heptanes.
Asunto(s)
Azetidinas/síntesis química , Paladio/química , Compuestos de Espiro/síntesis química , Aminación , Azetidinas/química , Catálisis , Ciclización , Estructura Molecular , Piperazina , Piperazinas/química , Compuestos de Espiro/química , EstereoisomerismoRESUMEN
Due to their direct influence on the stability of bacterial biofilms, a better insight into the nanoscopic spatial arrangement of the different extracellular polymeric substances (EPS), e.g., polysaccharides and proteins, is important for the improvement of biocides and for process optimization in wastewater treatment and biofiltration. Here, the first application of a combination of confocal laser-scanning microscopy (CLSM) and atomic force microscopy (AFM) to the investigation of river-water biofilms and related biopolymers is presented. AFM images collected at selected areas of CLS micrographs dramatically demonstrate the heterogeneity of biofilms at the nanometer scale and the need for a chemical imaging method with nanoscale resolution. The nanostructures (e.g., pili, flagella, hydrocolloids, and EPS) found in the extracellular matrix are classified according to shape and size, which is typically 50-150 nm in width and 1-10 nm in thickness, and sets the demands regarding spatial resolution of a potential chemical imaging method. Additionally, thin layers of the polysaccharide alginate were investigated. We demonstrate that calcium alginate is a good model for the EPS architecture at the nanometer scale, because of its similar network-like structure.